Clinical Progress of Antibody-Drug Conjugates

 

Today, there are about 80 ADCs in clinical development, with 2 to 3 novel ADCs likely to be approved within the next few years. The clear clinical benefit of ADCs is only overshadowed by its dose-limiting toxicities, but recent improvements in technology combined with clinical data from past ADC programs and related fields are helping to shape the next generation of bioconjugates. At CHI's Clinical Progress of Antibody-Drug Conjugates conference, we invite scientists to share their clinical updates and and lessons learned that can help inform next-generation ADC design and development.

Thursday, September 3

12:40 pm

Antibody-Drug Conjugates Industry Overview

John M Lambert, PhD, Consultant

LESSONS LEARNED FROM PAST ADC PROGRAMS AND RELATED FIELDS - PART I

12:45 pm KEYNOTE PRESENTATION:

Ugly Ducklings: Why Clinically Effective Antibody-Drug Conjugates May Not Look that Pretty (at First)…And How to Spot Them

Greg M. Thurber, PhD, Assistant Professor, Chemical Engineering & Biomedical Engineering, University of Michigan

The antibody drug conjugate (ADC) landscape has changed significantly as lessons from the clinic have returned to the bench. Here, I present a ‘systems’ approach for designing ADCs and describe when the most potent ADC in vitro, the most effective ADC in vivo, and/or the least toxic ADC in animal models may not be the most effective drug in the clinic. This ‘systems’ approach can help ensure the most clinically effective agents, often ‘ugly ducklings’ in the pipeline, thrive in the end.

1:05 pm

Microdistribution of Antibody Distribution in Clinical Trials Using Fluorescently Labeled Anti-EGFR Antibody in Multiple Tumor Types

Eben L. Rosenthal, MD, John and Ann Doerr Medical Director, Stanford University

Systemically-administered labeled antibodies in cancer patients prior to surgery has allowed us to successfully measure antibody concentration in normal and tumor tissues. The biggest impact of this strategy is the ability to localize the antibody within tissues at the cellular level. We hypothesize that near-infrared, fluorescently labeled antibodies can be leveraged to estimate the dose at which the antibody reaches maximal tumor saturation, most notably for antibody-drug conjugates.

1:25 pm

Modeling Target-Mediated Drug Disposition to Design More Effective Therapeutics

Donald E. Mager, PharmD, PhD, Professor & Vice Chair, Pharmaceutical Sciences, SUNY Buffalo

Target-mediated drug disposition (TMDD) is a case in which binding of a drug to its pharmacological target influences the pharmacokinetics of the drug. This phenomenon represents a major distribution/elimination process for many antibody-based constructs. This talk will review the basic tenets of TMDD, highlight how computational modeling of TMDD is being used to guide the design and development of antibodies and antibody-drug conjugates, and potential clinical implications of TMDD.

1:50 pm Refresh Break - View our Virtual Exhibit Hall

LESSONS LEARNED FROM PAST ADC PROGRAMS AND RELATED FIELDS - PART II

2:30 pm

A New Mechanism of Malignant Cell Resistance to Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)

Louis M. Weiner, MD, Professor & Director, Oncology, Lombardi Comprehensive Cancer Center, Georgetown University

ADCC provides a model for uncovering immune resistance mechanisms. We have continuously exposed different cancer cell lines to KIR-deficient NK92-CD16V effector cells and ADCC-promoting monoclonal antibodies. We show that the induction of ADCC resistance involves genetic and epigenetic changes that lead to a general loss of target cell adhesion properties required for the establishment of an immune synapse, killer cell activation, and target cell cytotoxicity. These findings have implications for resistance to diverse forms of cancer immunotherapy.

2:50 pm

Radiohapten Capture Radioimmunotherapy for Cures of Human Tumor Xenografts in Mice

Steven M. Larson, MD, Donna & Benjamin M. Rosen Chair, Lab Head, Molecular Pharmacology, Memorial Sloan Kettering Cancer Center

Over the past several years, we have developed an antibody-based platform approach for parenterally targeted radiotherapy with a goal of cures without histologic evidence of radiotoxicity in laboratory models of highly radioresistant solid tumors. Using a radiohapten capture system developed in collaboration with the Wittrup Laboratory of MIT, we have demonstrated proof of principle with beta- and alpha-emitting radionuclides in 3 solid tumors (antigen targets): neuroblastoma (GD2), breast cancer (Her 2), and colon cancer (A33).

3:10 pm LIVE Q&A:

Q&A and Session Wrap-Up

Panel Moderator:
Greg M. Thurber, PhD, Assistant Professor, Chemical Engineering & Biomedical Engineering, University of Michigan
Panelists:
Eben L. Rosenthal, MD, John and Ann Doerr Medical Director, Stanford University
Louis M. Weiner, MD, Professor & Director, Oncology, Lombardi Comprehensive Cancer Center, Georgetown University
Steven M. Larson, MD, Donna & Benjamin M. Rosen Chair, Lab Head, Molecular Pharmacology, Memorial Sloan Kettering Cancer Center
Donald E. Mager, PharmD, PhD, Professor & Vice Chair, Pharmaceutical Sciences, SUNY Buffalo
3:40 pm Close of Day

Friday, September 4

PROGRESS FROM THE CLINIC - PART I

9:05 am

Belantamab Mafodotin – Driving Innovation for Next-Generation Therapy in Multiple Myeloma

Axel Hoos, PhD, Senior Vice President, Therapeutic Area Head, Oncology, GSK

BCMA has become the leading new target for multiple myeloma with several BCMA-targeting agents in clinical development. GSK’s belantamab mafodotin is an antibody-drug conjugate which has recently completed a pivotal study in 4th line of treatment in patients with multiple myeloma. This presentation provides an update on the pivotal data and overall clinical program of belantamab mafodotin.

9:25 am

TRPH-222: A Next-Generation ADC Targeting CD22

Nancy J. Levin, PhD, Vice President, Development, Triphase Accelerator Corp.

TRPH-222 is a CD22-directed ADC, constructed via a novel, site-specific (SMARTag™) conjugation approach, resulting in highly controlled and reproducible drug loading. TRPH-222 is being studied in relapsed and/or refractory B cell lymphoma patients in a phase 1 clinical trial (NCT03682796); currently, the trial is enrolling patients in the dose-escalation phase, with promising tolerability, PK, and PD, as well as early signs of clinical efficacy in this single agent study.

9:45 am LIVE Q&A:

Q&A and Session Wrap-Up

Panel Moderator:
John M Lambert, PhD, Consultant
Panelists:
Axel Hoos, PhD, Senior Vice President, Therapeutic Area Head, Oncology, GSK
Nancy J. Levin, PhD, Vice President, Development, Triphase Accelerator Corp.
10:10 am Session Break
10:30 am Speed Networking Coffee Break - View our Virtual Exhibit Hall

PROGRESS FROM THE CLINIC - PART II

10:50 am

ZW49: Combining Zymeworks’ Platforms to Expand the Therapeutic Window of ADCs in HER2-Positive Cancer

Rupert Davies, PhD, Director, Translational Sciences, Zymeworks Biopharmaceuticals Inc.

HER2-targeted therapies have transformed the treatment of patients, but there remains a need for well tolerated and effective treatments across a range of HER2 expression levels. ZW49 is a bispecific antibody-drug conjugate that combines the ZymeLink™ linker-payload with the unique mechanisms of action of a biparatopic, anti-HER2 Azymetric antibody. ZW49 has the potential to address the unmet medical need across a range of HER2-expressing cancers.

11:10 am

Combining ADCs and Immunotherapy: Mechanistic Insights and Clinical Observations

Nancy C. Whiting, PhD, Executive Vice President, Development, Seattle Genetics, Inc.

MMAE-based ADCs have demonstrated the potential to change the natural history of multiple cancers. MMAE, the cytotoxic payload, has been shown to induce immunogenic cell death. Combining MMAE-based ADCs with immunotherapy has the promise of augmenting the benefit of each of these therapies.

11:30 am

Antibody-Drug Conjugates: Are We There Yet?

Anthony W. Tolcher, MD, FRCPC, FACP, CEO & Founder, NEXT Oncology

If success is measured by regulatory approval, then 2019 and 2020 were successful years for antibody drug conjugates. With the approvals of enfortumab vedotin-ejfv, polatuzumab vedotin-piiq, fam-trastuzumab deruxtecan-nxki, and more recently sacituzumab govitecan-hziy by the Food and Drug Administration in the past 18 months exemplifies how the platform has evolved over the last 25 years. I will review the clinical lessons learned and opportunities to broaden the field.

11:50 am

Q&A and Session Wrap-Up

Panel Moderator:
Nancy C. Whiting, PhD, Executive Vice President, Development, Seattle Genetics, Inc.
John M Lambert, PhD, Consultant
Panelists:
Rupert Davies, PhD, Director, Translational Sciences, Zymeworks Biopharmaceuticals Inc.
Anthony W. Tolcher, MD, FRCPC, FACP, CEO & Founder, NEXT Oncology
12:15 pm Close of Summit





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